The treatment of chronic moderate or severe pain is a difficult and sometimes unsuccessful medical challenge. Morphine and other opioid analgesics are often used to treat severe acute pain, but the development of tolerance, psychic and physical dependence, and potentially serious narcotic side effects limit their usefulness in treating chronic pain conditions. Antiinflammatory analgesics lack the strong analgesic efficacy of opioid analgesics and produce other serious side effects including gastrointestinal bleeding and gastric erosion that limits their usefulness in treating chronic severe pain.
Tricyclic antidepressant drugs are occasionally used as adjuncts in treating chronic pain associated with depressive disorders, but they lack the stronger analgesic potency of morphine-like drugs and produce potentially serious side effects of their own (A. G. Gilman, et al: Goodman and Gilman's The Pharmacological Basis of Therapeutics, Seventh Edition, Macmillan Publishing Co., New York, 1985). While tricyclic antidepressants are not recognized as primary analgesic agents, they are thought to modulate pain transmission via alterations in serotonin or norepinephrine uptake in the brain (S. Butler, Adv. Pain Res. Ther. 7:173-197, 1984).
Compounds of the invention show moderate-to-strong analgesic activity in mice, rats, and dogs. Unlike opioid analgesics, they lack activity at mu, kappa, delta, or sigma receptor sites in the brain. Studies in animals show that they lack the addictive and respiratory depressant properties of narcotic-related analgesics. Unlike antiinflammatory analgesics, they do not inhibit prostaglandin synthesase activity or show antiinflammatory effects in vivo. Like the tricyclic antidepressants, they inhibit uptake of serotonin, norepinephrine, and/or dopamine in rat brain preparations. However, analgesic doses of the compounds of the invention are not accompanied by anticholinergic side effects, sedation, or other signs of motor impairment observed with tricyclic antidepressants.
Many of the 4-arylpiperidinecarbinols of this invention, as shown below by Formula Ia, are known to have antidepressant activity. These compounds and methods for preparing them are disclosed in Ciganek, U.S. Pat. No. 4,485,109, issued Nov. 27, 1984, the disclosure of which is hereby incorporated by reference. ##STR1## wherein (a) R.sup.1 is H, alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or benzyl;
(b) each of R.sup.2 and R.sup.3 is independently selected from H and lower alkyl of 1 to 4 carbon atoms; R.sup.1 and R.sup.2 taken together is a branched or unbranched alkylene bridge wherein the bridge is of 3 or 4 carbon atoms; or R.sup.2 and R.sup.3 taken together is a branched or unbranched alkylene bridge wherein the bridge is of 3 to 6 carbon atoms; PA0 (c) R.sup.4 is PA0 (d) each of R.sup.5 and R.sup.6 is independently selected from alkyl of 1 to 12 carbon atoms and cycloalkyl of 3 to 8 carbon atoms or R.sup.5 and R.sup.6 taken together is a branched or unbranched alkylene bridge wherein the bridge is of 3 to 11 carbon atoms, PA0 Y is a hydroxymethyl (CH.sub.2 OH), hydroxyethyl or hydroxypropyl group, PA0 alk is an alkylene group (straight or branch-chain) containing up to six carbon atoms, and PA0 R is: PA0 X is H, or CH.sub.3 ; PA0 n=&gt;2&lt;5. PA0 J5,9106-460-A discusses antifungal and analgesic compounds of the formula ##STR4## wherein R.sup.1 and R.sup.3 .dbd.H, halogen, nitro or lower cycloalkyl; PA0 Q is --CO--, --CH(OH)--, or --O--radical; ##STR5## R.sup.4 is unsubstituted or halogenated phenyl, or pyridyl; R.sup.5 is H, protected carboxyl, carbamoyl or hydroxy-lower alkyl. PA0 R is CH.sub.2 OH amongst others; PA0 R.sub.1 is 1-4C alkyl. PA0 R.sup.1 is CH.sub.3, C.sub.2 H.sub.5, n-C.sub.3 H.sub.7, or allyl; PA0 R.sup.2 and R.sup.3 independently are H or alkyl of 1-4 carbon atoms; or R.sup.1 and R.sup.2 taken together is a branched or unbranched alkylene bridge wherein the bridge is of 3 or 4 carbon atoms; or R.sup.2 and R.sup.3 taken together is a branched or unbranched alkylene bridge wherein the bridge is of 3 to 6 carbon atoms; PA0 R.sup.4 is: PA0 R.sup.5 is alkyl of 1-4 carbon atoms, or is taken together with R.sup.6 to form a branched or unbranched alkylene bridge of 3-11 carbon atoms; PA0 R.sup.6 is H, alkyl of 1-4 carbon atoms, or is taken together with R.sup.5 to form a branched or unbranched alkylene bridge of 3-11 carbon atoms; and PA0 R.sup.7 is H, alkyl of 1-4 carbon atoms, alkanoyl of 1-4 carbon atoms, or --CH.sub.2 phenyl; or a pharmaceutically salt or N-oxide thereof, provided that when PA0 (1) R.sup.1, R.sup.5 and R.sup.6 are methyl, and R.sup.2 and R.sup.3 are H, then R.sup.4 is not 3,4-F.sub.2 C.sub.6 H.sub.3, 3,4-Cl.sub.2 C.sub.6 H.sub.3, p-t-butylphenyl, 2,3-(MeO)C.sub.6 H.sub.3, 2,5-(MeO).sub.2 C.sub.6 H.sub.3, or 3-pyridyl; PA0 (2) R.sup.1, R.sup.5 and R.sup.6 are methyl or R.sup.5 and R.sup.6 are taken together as --(CH.sub.2).sub.6 -- and --(CH.sub.2).sub.7, then R.sup.4 is not 3-MeOC.sub.6 H.sub.4. PA0 (2) when m is 1 or 3, or when R.sup.6 is H and m is 2; then R.sup.1 independently is CH.sub.3, C.sub.2 H.sub.5, n-C.sub.3 H.sub.7, or allyl;
(1) phenyl or 2-naphthyl or phenyl or 2-naphthyl substituted with one or two substituents, the same or different, selected from F, Cl, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, arylthio, perfluoroalkoxy, perfluoroalkylthio and dialkylamino, said alkyl and alkoxy moieties being of 1 to 12 carbon atoms and said aryl moieties being of 6 to 12 carbon atoms; PA1 (2) 2-, 3-, or 4-biphenyl or 2-, 3- 4-biphenylyl wherein either or both aromatic moieties are substituted with one or two substiuents, the same or different selected from F, Cl, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, arylthio, perfluoroalkoxy, perfluoroalkylthio and dialkylamino, said alkyl and alkoxy moieties being of 1 to 12 carbon atoms and said aryl moieties being of 6 to 12 carbon atoms; PA1 (3) 2-pyrrolyl or 2-pyrrolyl substituted with one to three lower alkyl groups of 1 to 4 carbon atoms; PA1 (4) 2-, 3-, or 4-pyridyl; or PA1 (5) 2-thienyl substituted in the 5-position with lower alkyl of 1 to 4 carbon atoms; PA1 (a) an alkoxy group containing up to six carbon atoms, or PA1 (b) an aryloxy group, or PA1 (c) an aralkoxy group, or PA1 (d) a group containing a heterocyclic oxygen atom, or PA1 (e) an aryl group, or PA1 (f) a heterocyclic residue carrying a basic nitrogen atom (e.g., pyridine, piperdine, morpholine, piperazine), or PA1 (g) an alkoxy group carrying a further oxygenated substituent such as a hydroxy, ethoxy or phenoxy group. PA1 (a) phenyl or ##STR8## where X is one or two substituents, the same or different, selected from F, Cl, Br, perfluoroalkyl, alkyl, alkyl- or dialkylamino, alkylthio, alkoxy or phenoxy, said alkyl in the alkyl-containing groups being of 1 to 12 carbon atoms; PA1 (b) 2-, 3-, or 4-biphenyl or 2-, 3-, or 4-biphenyl where either or both aromatic groups are substituted with 1 or 2 substituents, the same or different, selected from F, Cl, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, perfluoroalkoxy, arylthio, perfluoroalkylthio and dialkylamino, said alkyl and alkoxy groups being of 1-12 carbon atoms and said aryl groups being of 6-12 carbon atoms; PA1 (c) 1- or 2-naphthyl optionally having one or two X substituents as defined in (a) above; PA1 (d) 2-, 3-, or 4-pyridyl, or 2-, or 3-pyrrolyl optionally substituted with one to three alkyl groups of 1-4 carbon atoms; PA1 (e) 2- or 3-thienyl optionally substituted with one substituent selected from Cl, Br, or alkyl of 1-4 carbon atoms; or PA1 (f) 2- or 3-benzothienyl or benzofuryl optionally substituted on the aromatic ring with Cl, Br, or CF.sub.3 ; PA1 R.sup.4 is ##STR10## (b) 1-naphthyl optionally substituted with one or two substituents, the same or different, selected from F, Cl, Br; perfluoroalkyl, alkylthio, alkoxy, phenoxy, alkyl, alkyl- or dialkylamino, said alkyl in the alkyl-containing groups being 1-12 carbon atoms. PA1 (c) 3-pyrrolyl optionally substituted with one to three alkyl groups of 1-4 carbon atoms, PA1 (d) 2-, or 3-thienyl optionally substituted with Cl, Br, or alkyl of 1-4 carbon atoms, provided when 2-thienyl is substituted with alkyl it is other than the 5-position, or PA1 (e) 2-, or 3-benzothienyl or benzofuryl optionally substituted on the aromatic ring with Cl, Br or CF.sub.3 ; PA1 R.sup.5 independently is alkyl of 1-4 carbon atoms or when taken together with R.sup.6 is a branched or unbranched alkylene bridge of 3-11 carbon atoms; PA1 R.sup.6 independently is alkyl of 1-4 carbon atoms, or when taken together with R.sup.5 is a branched or unbranched alkylene bridge of 3-11 carbon atoms; PA1 R.sup.7 is H, alkyl of 1-4 carbon atoms, alkanoyl, or --CH.sub.2 phenyl; and PA1 R.sup.2 and R.sup.3 independently are H or alkyl of 1-4 carbon atoms; or R.sup.1 and R.sup.2 taken together is a branched or unbranched alkylene bridge wherein the bridge is of 3 or 4 carbon atoms; or R.sup.2 and R.sup.3 taken together is a branched or unbranched alkylene bridge where the bridge is of 3 to 6 carbon atoms; PA1 R.sup.4 is: PA1 (a) phenyl or ##STR11## where X is one or two substituents the same or different selected from F, Cl, Br, perfluoroalkyl, alkyl, alkyl- or dialkylamino, alkylthio, alkoxy or phenoxy, said alkyl in the alkyl-containing groups being of 1 to 12 carbon atoms; PA1 (b) 2-, 3-, or 4-biphenyl where either or both aromatic groups are substituted with 1 or 2 substituents, the same or different selected from F, Cl, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, arylthio, perfluoroalkoxy, perfluoroalkylthio and dialkylamine, amino, said alkyl and alkoxy groups being of 1-12 carbon atoms and said aryl groups being of 6-12 carbon atoms; PA1 (c) 1- or 2-naphthyl optionally having one or two X substituents as defined in (a) above; PA1 (d) 2-, 3-, or 4-pyridyl, or 2-, or 3-pyrrolyl optionally substituted with one to three alkyl groups of 1-4 carbon atoms; PA1 (e) 2- or 3-thienyl optionally substituted with one substituent selected from Cl, Br, or alkyl of 1-4 carbon atoms; or PA1 (f) 2- or 3-benzothienyl or benzofuryl optionally substituted on the aromatic ring with Cl, Br, or CF.sub.3 ; PA1 R.sup.5 independently is alkyl of 1-4 carbon atoms, or when taken together with R.sup.6 is a branched or unbranched alkylene bridge of 3-11 carbon atoms; PA1 R.sup.6 independently is H, alkyl of 1-4 carbon atoms, or when taken together with R.sup.5 is a branched or unbranched alkylene bridge of 3-11 carbon atoms; PA1 R.sup.7 is H, alkyl of 1-4 carbon atoms, alkanoyl, or --CH.sub.2 phenyl; or PA1 (a) R.sup.1 is CH.sub.3 ; or PA1 (b) R.sup.2 and R.sup.3 are H; or PA1 (c) R.sup.4 is 2- or 3-thienyl, or ##STR12## where X is Cl, Br, F, CF.sub.3 ; or (d) R.sup.5 is CH.sub.3 ; or PA1 (e) R.sup.6 is H or CH.sub.3 ; or PA1 (f) R.sup.7 is H. PA1 (a) R.sup.1 is CH.sub.3 ; or PA1 (b) R.sup.2, R.sup.3 and R.sup.7 are H; or PA1 (c) R.sup.4 is ##STR13## where X is Cl, Br, F or CF.sub.3 ; or (d) R.sup.5 is CH.sub.3 ; or PA1 (e) R.sup.6 is H or CH.sub.3. PA1 (a) 4-(3'-Chlorophenyl)-.alpha.,1-dimethylpiperidinemethanol (Example 1) PA1 (b) 4-(3'-Chlorophenyl)-.alpha.,.alpha.,1-trimethyl-4-piperidinemethanol (Example 1a) PA1 (c) 4-(3'-Bromophenyl)-.alpha.,1-dimethylpiperidinemethanol (Example 10) PA1 (d) 4-(3'-Bromophenyl)-.alpha.,.alpha.,1-trimethyl-4-piperidinemethanol (Example 41) PA1 (e) 4-(2-Thienyl)-.alpha.,1-dimethylpiperidinemethanol (Example 26) PA1 (f) 4-(3-Thienyl)-.alpha.,1-dimethylpiperidinemethanol (Example 27) PA1 (g) 4-(3'-Chlorophenyl)-.alpha.,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-azepine-1- methanol (Example 57) PA1 (h) 3-(3'-Chlorophenyl)-.alpha.,.alpha.,1-trimethyl-3-pyrrolidinemethanol (Example 56) PA1 (a) 4(3'-Chlorophenyl)-.alpha.,1-dimethylpiperidinemethanol (Example 1) PA1 (b) 4(4'-Trifluoromethylphenyl)-.alpha.-1-dimethylpiperidinemethanol (Example 16) or a pharmaceutically suitable salt thereof.
provided, however, when R.sup.1, R.sup.5 and R.sup.6 are methyl and R.sup.2 and R.sup.3 are H, then R.sup.4 is not p-t-butylphenyl or 2'-biphenylyl. The invention herein also resides in esters of the aforesaid piperidinecarbinols with aliphatic mono- and dicarboxylic acids of 1 to 8 carbon atoms, in amine salts of the aforesaid piperidinecarbinols with pharmaceutically compatible inorganic acids, and in N-oxides of the aforesaid piperidinecarbinols.
In addition to the references cited in the specification of U.S. Pat. No. 4,485,109, the following references appear to be particularly pertinent.
U.S. Pat. No. 3,108,111 to Stern et al., Nov. 22, 1963, discloses piperidine compounds useful as cough suppressants and analgesics of the formula ##STR2## where X is a phenyl group;
U.S. Pat. No. 3,080,372 to Janssen, Mar. 5, 1963, discloses pharmaceutically useful compounds of the formula ##STR3## wherein R is hydroxy (lower alkyl) amongst others;
BE 775,611 discloses 1-(3,3-diphenyl-1-propyl)-4-arylpiperidines as analgesics, spasmolytics and antitussive agents of the formula ##STR6## where Ar is Ph;
Several secondary piperidinecarbinols of the type described herein have been reported in the literature. Representative of these are M. A. Iorio et al., Tetrahedron, 4983 (1971); F. Bergel et al., J. Chem. Soc., 26, (1944); A. D. MacDonald et al., Brit J. Pharmacol., 1,4 (1946); A. L. Morrison et al., J. Chem. Soc., 1467, (1950); H. Kagi et al., Helv. Chim. Acta, 7,2489 (1949); U. Bondesson et al., Drug Metab. Dispos., 9, 376 (1981); U. Bondesson et al., Acta Pharm. Suec., 11, 1 (1980). There is no analgesic activity in any of these references other than in A. L. Morrison et al., which discloses that 4-phenyl-1-4-(1-hydroxyethyl)piperidine and 4-phenyl-1-methyl-4-(1-hydroxypropyl)piperidine were much less active as analgesics than the parent ketones.
There is no indication in the known art that the compounds of this invention would be useful as analgesics and be devoid of the anticholinergic side effects, sedation, or other signs of motor impairment observed with tricyclic antidepressants.